Gut Hormones in Adaptation

Gut: first published as 10.1136/gut.28.Suppl.31 on 1 January 1987. Downloaded from Gut, 1987, 28, SI, 31-35 Gut hormones in adaptation S R BLOOM From the Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London. SUMMARY The presence of a circulating factor affecting gut growth can be surmised from the findings in gut isolated from the main food stream and not under direct nutritional influence. Thus when a Thiry Vella fistula is constructed and the crypt cell production rate counted in the fistula it can be shown to correlate with the degree of resection of the main bowel left in continuity. The only hormones which become raised in a similar pattern are enteroglucagon and peptide tyrosine tyrosine (PYY). Enteroglucagon has been shown to be part of preproglucagon, which contains in addition oxyntomodulin, glucagon like peptide 1 1-37 and 6-36NH2 and glucagon like peptide 2. These form the main candidates for the 'hormone of gut growth'. Peptide tyrosine tyrosine has been tested by direct administration over 12 days, matching the natural rise, but no affect on crypt cell production rate was seen. Glucagon like peptide 1 1-37 was similarly tested and also found to produce no effect. It remains to test the other members of the glucagon family to confirm or refute the hypothesis that one of them is the enigmatic small gut growth factor. It is well recognised that after damage, for example by the control groups. All oral food was excluded from infection, the growth rate of the intestinal mucosa the second group which were only fed intravenously increases rapidly and that after small intestinal and gained slightly more weight than the other two http://gut.bmj.com/ resection the residual intestine hypertrophies. The groups. After 12 days all the animals were killed. Gut mechanism by which this adaptive growth is con- mucosal cell proliferation was determined by the trolled is less clear. One possibility is that it involves, stathmokinetic method using vincristine and crypt perhaps only in part, a circulating hormonal factor. cell microdissection to assess the crypt cell production Further this is most likely to come from the gut itself, rate.' In the control animals (transected) the crypt cell perhaps downstream from the region damaged or production rate (CCPR) in the terminal ileum was lost. 16f8 + 0-9 cells per crypt per hour. In the Thiry Vella on September 25, 2021 by guest. Protected copyright. fistula group (with 75 % bypassed gut) the rate in the Methods terminal ileum was much greater at 52 + 8. In the intravenously fed group, who had also undergone ANIMALS 75 % gut bypass, the rate was not significantly In an attempt to investigate the relative importance of different from the controls, however, at 18+5. This local factors, such as luminal nutrition and pan- showed, yet again, the direct or indirect importance of creaticobiliary secretions, as opposed to putative luminal nutrition. In the Thiry Vella fistula itself the circulating hormonal factors a series of rats were CCPR in the intravenously fed animals was studied in which a Thiry Vella fistula was fashioned. 160 + 15, not different from the normal terminal The external fistula comprised the proximal 75 % of ileum in the control animals, but significantly less the small bowel, measured from the ligament of than the CCPR in the Thiry Vella fistula of the orally Treitz, with the remaining bowel continuity being fed rats (23-8+2-8, p < 0-01).2 Thus in these experi- restored by an end to end anastomosis. The fistula ments there is a weak effect of a circulating factor was thus excluded from luminal nutrition and acting on the Thiry Vella fistula, which appeared to be pancreaticobiliary secretions. In a second group of dependent on luminal nutrition for its release from fistula rats a cannula was, in addition, inserted into the bowel in continuity. In a further similar series of the superior vena cava via the internal jugular vein experiments a smaller Thiry Vella fistula was con- and exteriorised at the back ofthe neck. A third series structed allowing groups of rats with 25%, 50%, of rats had merely a jejunal transection and formed 75 %, and 90 % resection of the bowel in continuity. Address for correspondence: Professor S R Bloom, Dept of Medicine, RPMS, Once again the Thiry Vella fistula was found to have Hammersmith Hospital, Du Cane Road, London W12 OHS a lower basal crypt cell production rate (10+ 1) less 31 Gut: first published as 10.1136/gut.28.Suppl.31 on 1 January 1987. Downloaded from 32 Bloom Discussion In 1971 a patient with intestinal mucosal hypertrophy was studied4 who had a resectable enteroglucagon producing tumour5 after which the hypertrophy disappeared. Enteroglucagon was therefore proposed as 'growth hormone to the small intestine'.6 Sub- sequently enteroglucagon was found to correlate with crypt cell production rate in a number of animal models of intestinal adaptation.7 '3 In the two Thiry Vella fistula models, mentioned above, entero- pmol/ I glucagon concentrations rose in proportion to the Thiry Vella fistula increase in crypt cell production rate.'14' 5Although a preliminary study suggested a direct trophic effect of partially purified enteroglucagon on cultured guinea pig jejunal mucosa'6 no -004- definitive study has yet firmly proven the trophic -I action of enteroglucagon. In man there is extensive >-jI correlation between a rise in enteroglucagon and Controls circumstances where increased enterocyte turnover would be expected - for example, after gut resection, ib3Test meal acute infective diarrhoea (Fig. 1), jejunoileal bypass, coeliac disease, tropical malabsorption, cystic fibrosis and, in the newborn, after initiation of enteral feed- Time (min) ing 17-27 Fig. 1 Plasma enteroglucagon responses to a 530 calorie Recently the human pre-pro-glucagon sequence test breakfast in 12 patients with acute diarrhoea and 13 has been derived and two additional glucagon like healthy controls (from 21). peptides discovered (Fig. 2).28 The first of these http://gut.bmj.com/ (GLP1) was also found in the angler fish pre-pro- glucagon29 and its sequence was approximately than the ileum in continuity (16 + 2). The CCPR in equally conserved to that of pancreatic glucagon the fistula rose, however, with increasing resection of itself. Thus over five hundred million years the forces the bowel in continuity and had doubled in the 90 % of evolution have retained, virtually unchanged, two resection group to 35 + 2 (p < 0-001).3 This clearly peptides with similar sequence suggesting that both showed the of a likely presence circulating factor must be necessary for survival. Enteroglucagon was on September 25, 2021 by guest. Protected copyright. affecting mucosal growth but gave no information on sequenced in 198130 and shown to be composed of 69 its possible interaction with luminal nutriments at the amino acids and to contain the entire sequence of target site as the studied Thiry Vella fistula received pancreatic glucagon towards its C-terminal terminus. no luminal stimulant. It is conceivable, but unproven, In the alpha cell of the pancreas pre-pro-glucagon that even a small amount of luminal nutriment undergoes post-translational enzymic processing to stimulation might have greatly enhanced the effec- cleave out pancreatic glucagon, no enteroglucagon tiveness of the putative circulating growth factor or being formed.3' In contrast the two gluca,on-like factors on the fistula mucosa. peptides, GLP1 and GLP2, are mostly not separated Enteroglucagon (69aa) ------I NH2-peptide Glucagon Pre-(20aa) (30aa) (29aa) (6aa) GLP-1 (37aa) (13aa) GLP-2(35aa) I I 1.. l cm m Lm .- ^, \ _~~~~~~t cm1- cn L-v} 03 -J cm > VA cn vw -I . -J Fig. 2 Scheme showing the regions of the pre-pro-glucagon molecule. Gut: first published as 10.1136/gut.28.Suppl.31 on 1 January 1987. Downloaded from Gut hormones in adaptation 33 50* have been tested as the amounts of the various GLPs Infective diarrhoea (n=12) that would be required to produce significant long 40- term effects in animals would, at the present time, be very expensive. Preliminary tests on isolated cultures 0 E _-F-1--_ ' have not proved positive but the GLP's action has not -9 30- yet been exhaustively investigated. a- Only the gut glucagon system correlates well with a E 20- gut growth and hitherto other hormonal systems, U, I L I Healthy controls (n=15) including gastrin, cholecystokinin, gastric inhibitory a. polypeptide, motilin, neurotensin, secretin, and other 10- local gut peptides have not been observed to be associated with this phenomenon. Recently a further 0- gastrointestinal peptide was isolated and termed 6 60 20 180 peptide tyrosine tyrosine (PYY using the IUPAC Tirne (minI shorthand nomenclature).35 This peptide was found Fig. 3 Plasma PYY concentrations aturing a 530 calorie to be present in endocrine cells of the intestinal test breakfast in 12 patients with acut e infective diarrhoea mucosa, where it is costored with the gut glucagon and 15 healthy controls (from 39). peptides in at least a proportion of the endocrine cells.36 In man it was found to have a very similar 10011 distribution to enteroglucagon, being present in high Ileal resection (n=8) concentrations in the mucosa of the large bowel and distal small intestine.37 It was not found else- z80 ------ where in the body. It was also found to be released E .1- 1.. by long chain fatty acids and carbohydrates, in a 0. -60 similar manner to enteroglucagon. Indeed in all the bowel diseases which caused a rise in enteroglucagon a in man PYY was also found to be very raised (Fig. 3 E 40- http://gut.bmj.com/ U) and Fig.

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